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bioRxiv · 10.1101/2025.10.23.684096

Single-Cell Immune Profiling Reveals Non-classical Monocyte-Driven Immunodepression in Tuberculosis Treatment Non-Responders

Che, Y.·Xiong, Y.·Zhang, D.·Qu, Y.·Shen, H.·Wang, W.·Gao, J.·Wang, Z.·Chen, Y.·Shen, Z.
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Abstract

Sputum culture conversion (SCC) at 2 months is a critical predictor of tuberculosis (TB) treatment outcomes, yet the underlying immune alterations driving treatment non-response remain unclear. We performed single-cell RNA sequencing on peripheral blood mononuclear cells from 8 TB patients, stratified by 2-month SCC status, to characterize cellular heterogeneity and intercellular communication. Treatment non-responders exhibited marked expansion and terminal differentiation of non-classical monocytes with elevated TB progression risk signatures. These cells showed reduced outgoing but enhanced incoming signaling, prominently via IL-16 and TRAIL pathways, potentially amplifying regulatory T cell (Treg)-mediated immunosuppression. CD4 Tregs in non-responders engaged in intensified GALECTIN signaling toward CD8 cytotoxic T cells and mature NK cells, contributing to effector cell exhaustion. NK cell subsets, particularly mature NK c2, displayed increased inhibitory receptor expression and terminal differentiation states. Our findings delineate a dysregulated "non-classical monocyte -Treg -cytotoxic lymphocyte" axis in TB treatment failure, highlighting candidate biomarkers and host-directed therapeutic targets.

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Che, Y., Xiong, Y., Zhang, D., Qu, Y., Shen, H., Wang, W., Gao, J., Wang, Z., Chen, Y., Shen, Z.. 2025-10-24. Single-Cell Immune Profiling Reveals Non-classical Monocyte-Driven Immunodepression in Tuberculosis Treatment Non-Responders. https://doi.org/10.1101/2025.10.23.684096

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